The main goal of the proposed research is to determine how the central nervous system actions of nicotine and the sensory/behavioral aspects of cigarette smoking contribute to tobacco dependence. In the proposed work, the central pharmacologic effects of smoking will be delivered without the usual sensory and behavioral cues, using intravenous (i.v.) nicotine infusions; conversely, the sensory and behavioral components of the smoking habit will be conveyed without pharmacologic actions, using de-nicotinized cigarettes. By dissociating and independently varying these two key components, we will gain a better understanding of how they interact in affecting the reinforcement processes mediating smoking behavior and the regulation of nicotine intake. Laboratory studies will assess the relative roles of nicotine dose and sensory/behavioral cues on smoking satisfaction, relief of smoking withdrawal symptoms, and on smokers' ability to self-titrate nicotine intake. The ability of smokers to discriminate between rapid nicotine injections and slower continuous nicotine infusions will be examined. In addition to participating in the laboratory studies, the same subjects will be able to enroll in a smoking cessation program using nicotine skin patch therapy. Responses to i.v. nicotine and to the sensory/behavioral cues in the laboratory studies will be correlated with the clinical response to nicotine replacement treatment. This will lead to a better understanding of the role of pharmacologic and sensory/behavioral cues in nicotine addiction and smoking cessation. Future plans include the assessment of behavioral preference between the pharmacologic effects of nicotine and the sensorimotor aspects of smoking, the dissociation of central vs peripheral nicotine receptors in the reinforcing effects of cigarette smoking using selective antagonists, and measurement of the ability of smokers to regulate nicotine intake based on central and/or peripheral cues.